Selective Neuronal Vulnerability to Proteinopathy

A defining feature of neurodegenerative diseases is selective neuronal vulnerability, in which specific populations of neurons are susceptible to pathogenic processes that lead to aberrant protein aggregation, degeneration, and eventual cognitive decline. Although decades of research has shed light on the identity of selectively vulnerable neurons, the precise molecular underpinnings that render neurons susceptible or resilient to proteinopathy remain elusive.

Topics of interest in the lab:

One of the major research interests in the Condello lab is to understand the molecular basis of selective neuronal vulnerability to proteinopathies, with a particular focus on tau aggregation and neuron loss in the context of ADRDs. More specifically, we are keen on studying early-affected brain regions to gain insight into the cellular responses to proteopathic pressure at the onset of pathology. Our current projects within this research track are:

1. Multi-modal profiling of selectively vulnerable neurons in transgenic models of tauopathy and Human ADRDs
   • We are taking a multi-modal approach to studying selectively vulnerable neurons through use of single nucleus RNA sequencing, spatial transcriptomics, metabolomics and confocal microscopy.
   • We are applying this workflow to characterize vulnerable neurons within our novel rat model of tauopathy. This transgenic line, termed Tg12099, recapitulates the spatio-temporal pattern of tau pathology and neuron loss seen in human ADRDs, including progressive tau aggregation in the entorhinal cortex and hippocampus.

• In parallel, we are leveraging similar single cell and spatial approaches to study the entorhinal cortex in human Alzheimer’s Disease cases
  
  2. Mechanisms of tau processing and proteostasis

  • Investigating how different modifications of tau (truncation, phosphorylation, ubiquitination) relate to aggregation and vulnerability 

  • Targeting these pathways as a potential for interventional treatment. We are actively collaborating with the Arkin lab and the Renslo Lab at UCSF for this work.

  • Testing roles of tau proteostasis machinery and metabolic pathways in collaboration with Martin Kampmann.

    

Through this on-going work, our lab seeks to define the spatially-distinct molecular signatures of vulnerable and resilient neurons, and how these signatures support or inhibit proteinopathy.